www.elsevier.com/locate/autneu

Autonomic Neuroscience: Basic and

Effects of long-term angiotensin converting enzyme inhibition on

cardiovascular variability in aging rats

Valdo Jose Dias da Silva a, Nicola Montano b, Helio Cesar Salgado c, Rubens Fazan Junior c,*

a Department of Biological Sciences, School of Medicine of Triangulo Mineiro, Uberaba, MG Brazilb Department of Clinical Sciences, Internal Medicine II, L. Sacco Hospital, University of Milan, Milano, Italy

c Department of Physiology, School of Medicine of Ribeirao Preto, Av. Bandeirantes 3900, 14049-900, Ribeirao Preto, SP, Brazil

Received 20 July 2005; received in revised form 28 November 2005; accepted 28 November 2005

Abstract

We studied the effects of chronic (4 weeks) angiotensin converting enzyme inhibition with captopril on arterial pressure (AP) and heart rate

(HR) variability, as well as on cardiac baroreflex sensitivity (BRS), in aged (20 months) rats. Series of basal RR interval (RRi) and systolic AP

(SAP) were studied by autoregressive spectral analysis with oscillations quantified in low (LF: 0.2–0.8 Hz) and high frequency (HF: 0.8–

2.5Hz). BRSwasmeasured by linear regression betweenHR andMAP changes. Captopril did not affect the spectra of RRi or SAP in young rats.

Aged rats presented a reduction in variance (time domain) and in LF and HF oscillations of RRi and SAP. Captopril induced, in aged rats, a

decrease in absolute and normalized LF oscillations and in LF/HF ratio of RRi. Captopril also reduced the variance, without changing its LF or

HF components of SAP. Reflex tachycardia was reduced in aged as compared to young rats (�1.1T0.2 versus �3.4T0.5 bpm/mm Hg) and

captopril did not affect it. Reflex bradycardia was also reduced in aged rats (�0.7T0.5 versus�2.0T0.4 bpm/mm Hg), but captopril prevented

this attenuation in aged rats (�2.3T0.3 versus�0.7T0.5 bpm/mm Hg). These data indicate that there is a reduction in HR and SAP variability

during aging, suggesting impairment of cardiovascular autonomic control. Captopril was able to change the power of oscillatory components of

RRi, suggesting a shift in cardiac sympatho/vagal balance toward parasympathetic predominance. In addition, blockage of ACE improved the

reflex bradycardia, but not the reflex tachycardia in aged rats.

D 2005 Elsevier B.V. All rights reserved.

Keywords: Aging; Heart rate variability; Baroreceptor; ACE inhibitor; Rats

1. Introduction

Aging is associated with an impairment of arterial

pressure regulation which is expressed by an increased

arterial pressure variability (Shi et al., 2003; Laitinen et al.,

2004) and tendency to postural and postprandial hypoten-

sion (Ferrari et al., 2003). In addition, it is well known that

aging is associated with a reduction of heart rate variability

(Ferrari et al., 2003) and depression of cardiac baroreflex

sensitivity (BRS) in both humans (Gribbin et al., 1971;

Jones et al., 2003) and animals (Ferrari et al., 1991; Irigoyen

et al., 2000).

1566-0702/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.autneu.2005.11.004

* Corresponding author. Tel.: +55 16 36023331; fax: +55 16 36330017.

E-mail address: rfazanjr@rfi.fmrp.usp.br (R. Fazan Junior).

The attenuation of baroreflex control of heart rate (HR)

during aging (Gribbin et al., 1971; Ferrari et al., 1991, 2003;

Sei et al., 2002; Jones et al., 2003; Nagai et al., 2003) could

be involved in higher arterial pressure variability (Laitinen

et al., 2004), orthostatic intolerance (Sei et al., 2002;

Laitinen et al., 2004), reduced vagal control of the heart

(Ferrari et al., 2003; Shi et al., 2003) and increased

sympathetic nerve activity to the heart and vessels (Ferrari

et al., 2003). All these alterations might be associated with

electrical and morphological changes of myocardium which

significantly increase the incidence of life-threatening

cardiac arrhythmias and sudden death in aged subjects

(Molander et al., 2003; Kistler et al., 2004; Souza Neto et

al., 2004). Accordingly, therapeutic strategies which im-

prove reduced heart rate variability and cardiac baroreflex

Clinical 124 (2006) 49 – 55

V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–5550

dysfunction related to aging should be useful to decrease

cardiovascular-related morbidity and mortality.

Experimental and clinical studies have demonstrated that

ACE inhibitors decrease efferent sympathetic nerve activity

(Montano et al., 1993), increase cardiac baroreflex sensi-

tivity in both animals (Ichikawa et al., 1995) and humans

(Williams and Kim, 2003) with hypertension or congestive

heart failure. These drugs act through inhibiting the

conversion of angiotensin I into angiotensin II, blocking

the endogenous renin–angiotensin system (Brunner et al.,

1996). In addition, other vasodilators can be generated by

ACE inhibitors, especially bradykinin (Linz et al., 1995;

Izzo, 2000).

Studies performed in animals, especially rats, evaluated

the effects of ACE inhibitors on aging. ACE inhibitors

produced, in old rats, a variety of benefits, such as:

reduction in renal intravascular resistance and proteinuria

(Heudes et al., 1994), reduction in the thickness of media

and intima layer of large arteries (Michel et al., 1994);

improvement of endothelial function of resistance vessels

(Lang et al., 1995), and improvement of the autoregulatory

mechanism of cerebral blood flow (Lartaud et al., 1994).

With respect the effects of ACE inhibitors on aging-related

cardiac baroreflex dysfunction, in rats, treatment with the

ACE inhibitor lisinopril, during 1 month, increased reflex

bradycardia in both young (4 months) and aged (21 months)

rats (Bunag et al., 1999). However, in this study, the effect

of the ACE inhibitor was not examined on the reflex

tachycardia.

The effects of ACE inhibitors on arterial pressure (AP)

and heart rate variability have been studied extensively in

patients under several conditions, e.g. arterial hypertension

(Tomiyama et al., 1998; Guasti et al., 2001), chronic heart

failure (Binkley et al., 1993) and cardiac surgery (Souza

Neto et al., 2004). To our knowledge there are only a few

studies examining the effects of ACE inhibitors on the

sympatho/vagal balance (Grichois et al., 1992; Rimoldi et

al., 1994). Studies of HR variability in young adult rats

described no effect (Grichois et al., 1992) or an increase

(Ponchon and Elghozi, 1996) in the cardiac sympathetic

activity after inhibition of renin–angiotensin system.

However, to our knowledge, the effects of ACE inhibitors

on aging-related changes in AP and HR variability were not

investigated yet in aged rats.

Therefore, the present study was designed to examine, in

24-month aged rats, the effects of chronic ACE inhibition,

by means of captopril, on: (1) arterial pressure and heart rate

variability; (2) cardiac baroreflex sensitivity.

2. Methods

Four-month-old male Wistar rats were separated into the

following groups: young rats treated with captopril (N =8), or

tap water (N =8), during 2 months; aged rats treated with

captopril (N =7), or tap water (N =5), during 20 months.

Treatment with captopril consisted of a solution (0.5 mg/mL)

dissolved in tap water, supplied ad libitum during 2 months

for the young group, or during 20 months for the aged group.

The animals drank approximately 20–30 mL/day of the

captopril solution, receiving approximately 30 mg/kg of

captopril daily. This dosage has been used in different

pharmacokinetic and pharmacodynamic studies in rats to

evaluate its cardiovascular effects (Wilson et al., 1988; Sun

and Mendelsohn, 1991). Age matched untreated groups

received only tap water during the same period, i.e. 2 or

20 months. Body weight and fluid intake were continuously

monitored during the treatment period. All surgical proce-

dures and protocols were in accordance with the Guidelines

for Ethical Care of Experimental Animals.

At the end of 2- or 20-month period, the animals were

instrumented, under tribromoethanol (250 mg/kg, i.p.)

anesthesia, with catheters implanted into the femoral artery

and vein, and ECG electrodes (lead II) implanted into the

subcutaneous tissue. After the surgical procedures the

animals recovered in individual cages for at least 24 h.

After recovery the arterial catheter was connected to a

pressure transducer (Statham P23Gb, Hato Rey, PR, USA)

and the signals of arterial pressure (AP) and ECG were

amplified and continuously sampled (1000 Hz) in an IBM/

PC equipped with a 12 bit analogic to digital interface

(CAD12/36 Lynx Eletronica, Sao Paulo, Brazil). During the

experiment silence was maintained inside the room to avoid

the influence of stress on AP and ECG recording.

After at least 30 min of basal pulsatile AP and ECG

recording, the animals received intravenous injection of

angiotensin I (100 ng/kg, i.v. bolus) to verify the efficacy of

ACE blockade by captopril. Only animals treated with

captopril showing a pressor response to angiotensin I

smaller than 5 mm Hg were included in this study.

Approximately 15 min after the test with angiotensin I,

the animals received, randomly, i.v. bolus injections of

phenylephrine (0.25–8 Ag/kg) or sodium nitroprusside (1–

32 Ag/kg) to change AP in order to evaluate the cardiac

baroreflex. At the end of the experiments the animals were

killed by ether inhalation.

AP and ECG recordings were processed by a customized

computer software that applies an algorithm to detect cycle-

to-cycle inflection points in the pulsatile AP signal,

determining beat-by-beat values of systolic and diastolic

pressures. Beat-by-beat RR interval (RRi) series from ECG

were also generated by measuring the length of time

between adjacent R waves. From baseline 30 min recording

period, the time series of RR interval and systolic AP were

divided into contiguous segments of 300 beats, overlapped

by half. After the calculations of mean and variance of each

segment they were submitted to a model-based autoregres-

sive spectral analysis as described elsewhere (Malliani et al.,

1991; Rubini et al., 1993; Task Force, 1996). Briefly, a

modeling of the oscillatory components presented in

stationary segments of beat-by-beat time series of SAP

and RRi was calculated based on Levinson-Durbin recur-

V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–55 51

sion, with the order of the model chosen according to

Akaike’s criterion (Malliani et al., 1991). This procedure

allows an automatic quantification of the center frequency

and power of each relevant oscillatory component present in

the time series. The oscillatory components were labeled as

very low (VLF), low (LF) or high frequency (HF) when

their central frequency were within a band of 0.01–0.20,

0.20–0.75 or 0.75–2.50 Hz, respectively. The power of LF

and HF components of heart rate variability was also

expressed in normalized units, obtained by calculating the

percentage of the LF and HF variability with respect to the

total power after subtracting the power of the VLF

component (frequencies <0.20Hz). The normalization pro-

cedure tends to minimize the effect of the changes in total

power on the absolute values of LF and HF variabilities

(Malliani 1991, Rubini et al., 1993; Task Force, 1996).

Baroreflex sensitivity was quantified by the slope of the

regression line obtained by best-fit points relating changes

in RRi and SAP with respect to their baseline values.

Data are expressed as meanTS.E.M. Two-way analysis

of variance followed by a Tukey’s multiple comparison test

was performed to evaluate the effects of treatment (captopril

versus tap water) and age (young versus aged). The

differences were considered significant when P <0.05.

3. Results

Untreated aged rats were significantly heavier than the

untreated young rats (512T22 versus 461T15 g, P <0.05).

On the other hand, aged and young rats treated with captopril

had similar body weights (434T26 versus 460T24 g,

respectively). Aged rats treated with captopril weighed less

than their untreated counterparts (434T26 versus 512T22,respectively P <0.01).

Baseline values of mean arterial pressure (MAP) and HR

from conscious rats are shown in Table 1. MAP and HR

were significantly lower in aged rats treated with captopril

as compared to the other groups.

The pressor response to angiotensin I in young untreated

rats was 35T3 mm Hg while in young rats treated with

captopril it was 4T2mmHg (P <0.001), an attenuation of the

pressor response of approximately 89%. The pressor re-

Table 1

Baseline values (meanTS.E.M.) of systolic (SAP), diastolic (DAP) and

mean arterial pressure (MAP) and heart rate (HR) in conscious young and

aged rats treated (Captopril) or not (Untreated) with captopril

Young Aged

Untreated

(N =8)

Captopril

(N =8)

Untreated

(N =5)

Captopril

(N =7)

SAP (mm Hg) 126T4 131T5 138T4 131T4

DAP (mm Hg) 69T3 73T4 77T2 62T3*

MAP (mm Hg) 89T2 93T4 97T2 85T2*

HR (bpm) 381T11 374T15 405T11 311T25*

* P< 0.05 versus aged untreated rats.

sponse to angiotensin I in aged untreated rats was 68T18 mm

Hg while in aged rats treated with captopril it was 1T2 mm

Hg (P <0.0001), an attenuation of the pressor response of

approximately 98%.

Fig. 1 shows representative spectra of RRi and SAP of

young and aged rats treated or not with captopril. The

spectral pattern of RRi and SAP of young rats were not

affected by captopril (Fig. 1, Table 2). As compared to

young rats, untreated aged rats presented a significant

reduction, not only in variance, but also in LF and HF

oscillations of RRi and SAP variability (Table 2). Captopril

induced, in aged rats, a decrease in both, absolute and

normalized LF component, and also in LF/HF ratio of RRi

(Table 2). Captopril also reduced the SAP variance, in aged

rats, without changing SAP LF or HF components (Table 2).

Reflex bradycardia and tachycardia induced by the

increase, or decrease, in MAP were not different between

young rats treated, or not, with captopril (Fig. 2). The reflex

tachycardia was significantly reduced in aged untreated rats

as compared with young untreated rats (�1.1T0.2 versus

�3.4T0.5 bpm/mm Hg, P <0.05). Captopril did not affect

the reduced reflex tachycardia of aged rats (�1.1T0.4 bpm/

mm Hg versus �1.1T0.2 bpm/mm Hg in aged untreated

rats, P <0.05). The reflex bradycardia was also significantly

reduced in aged untreated rats as compared with young

untreated rats (�0.7T0.5 versus �2.0T0.4 bpm/mm Hg,

P <0.05). However, captopril prevented the attenuation of

the reflex bradycardia of aged rats (�2.3T0.3 bpm/mm Hg

versus �0.7T0.5 bpm/mm Hg in aged untreated rats,

P <0.05).

4. Discussion

The results of the present study indicate that during the

aging process, in rats, there is a significant reduction in HR

and SAP variability, suggesting an impairment of the

autonomic modulation of the cardiovascular system. Al-

though long-term ACE inhibition with captopril did not

prevent the reduction of HR and SAP variability, it was able

to change the power of oscillatory components of RRi,

shifting the cardiac sympatho/vagal balance towards a

parasympathetic predominance. In addition, blockage of

ACE improved the reflex bradycardia, but not the reflex

tachycardia in aged rats.

Despite that plasma and tissue renin activities were not

evaluated, the attenuation (82% and 98%) of the pressor

response elicited by angiotensin I indicated that chronic

treatment with captopril was effective to block ACE,

leading to a decreased activity of the renin–angiotensin

system.

Young untreated rats presented a MAP within the range

expected for their age, i.e. 6 month olds; a value not

significantly different was observed for aged untreated rats.

These findings indicate that basal MAP of rats did not

change, significantly, during 24 months of aging. Chronic

Fig. 1. Examples of representative autoregressive spectra calculate from series of RR interval (ms2/Hz, top) and systolic arterial pressure (mm Hg2/Hz, bottom)

of young and aged rats, untreated or chronically treated, with captopril. PSD=power spectral density.

V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–5552

treatment with captopril did not affect the MAP of young

rats, but decreased, significantly, the MAP of aged rats, as

compared to their untreated counterparts. The mechanism of

the reduction of MAP of aged rats by means of captopril

was not examined in the present study. A possible

Table 2

Spectral parameters of RR interval (RRi) and systolic arterial pressure

(SAP) calculated from time series using autoregressive spectral analysis

Young Aged

Untreated

(N =8)

Captopril

(N =8)

Untreated

(N =5)

Captopril

(N =7)

SAP

Variance (mm Hg2) 20.0T4.4 19.9T4.4 2.0T0.7T 1.3T0.5TLF (mm Hg2) 6.2T1.4 7.0T1.2 0.5T0.4T 0.5T0.3THF (mm Hg2) 7.0T2.1 7.1T2.0 0.4T0.1T 0.4T0.2T

RRi

Variance (ms2) 27T8 31T8 17T6T 11T6TLF (ms2) 1.9T0.6 2.3T0.6 1.2T0.4T 0.2T0.1T.LF (nu) 18T2 19T2 22T4.5 9T3T.HF (ms2) 7.2T1.6 8.2T1.6 4.7T1.7T 3.8T2.3THF (nu) 82T2 81T2 78T4 91T3T.LF/HF ratio 0.2T0.1 0.2T0.1 0.3T0.1 0.1T0.1T.

All values were expressed as meanTS.E.M.

TP <0.05 versus young untreated rats, .P <0.05 versus aged untreated rats.

‘‘nu’’ indicates normalized units.

explanation may involve an increase in sensitivity to RAS

stimulation as observed in the kidneys of early aging rats

(Thompson et al., 2000), which could make aged rats more

sensitive to blockage of ACE in peripheral tissues.

In the present study we are not able to detect a significant

difference in baseline HR among young and aged rats.

Despite of the small number of animals, this finding seems

to confirm previous observations from the literature (Tanabe

and Bunag, 1989; Werner et al., 1995, Irigoyen et al. 2000).

Despite that Berg (1955) found no changes in HR in rats 7

to 18 months old, a lower HR was found in rats 28 to 31

months old. In the present study, prolonged (20 months)

ACE inhibition with captopril reduced the basal HR of aged

rats as compared with aged untreated rats. This finding may

be related to changes of the sympatho/vagal balance to the

heart, with a predominance of vagal activity in aged rats

submitted to chronic ACE inhibition with captopril.

Aged untreated rats exhibited a smaller variability of HR

as compared with young untreated rats. The reduced

variability of HR is demonstrated by the significant

attenuation of variance, which quantified the total variability

of the time series of RRi. The spectral analysis of HR

variability displayed also a significant reduction of the HF

band, which is widely accepted as a marker of vagal

modulation of the heart associated with respiratory sinus

Fig. 2. Group data of reflex changes in heart rate (HR) due to induced changes in mean arterial pressure (MAP) in young and aged rats receiving captopril (open

circles, dotted line), or tap water (solid circles, solid line). Lines represent the linear regressions between changes in heart rate and mean arterial pressure. The

slope of linear regression was used as the index of the baroreflex sensitivity. TP <0.05 compared to rats treated with captopril. TTP <0.01 compared to young

rats.

V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–55 53

arrhythmia (Akselrod et al., 1981; Malliani et al., 1991;

Task Force, 1996). This finding suggests an impairment of

vagal modulation of the heart of aged untreated rats,

providing support to previous data from the literature which

demonstrate an impaired vagal function during aging

process (Kelliher and Conahan, 1980).

On the other hand, a remarkable reduction of total

variability (variance) and spectral components (LF and HF)

of SAP was observed in aged untreated rats, as compared

with their young counterparts. In contrast to the findings in

old human beings who display an increased variability of the

arterial pressure attributed to a derangement of the baroreflex

(Mancia et al., 1985), the results of a reduced variability of

SAP observed in aged untreated rats may suggest a loss of

autonomic control of the peripheral vessels associated with

aging, since the normal variability of AP depends of an intact

autonomic nervous system. However, we cannot discard

other mechanisms, e.g. as angiotensin II, physical activity,

etc. Previous data in animals and humans have suggested that

AP fluctuations, mainly in very low frequency range, may

depend on modulation of vasomotor tone by humoral

substances such as angiotensin II (Akselrod et al., 1981;

Dutrey-Dupagne et al., 1991). Because the renin–angioten-

sin system is less active in the elderly (Hayduk et al., 1973),

it could contribute to a lower total SAP variability observed

in untreated aged rats. Other data also suggest that AP and

HR oscillations depend on physical activity (Bernardi et al.,

1996). As spontaneous physical activity declines with age

(Dawson and Crowne, 1988), it could also contribute to the

marked reduction in total SAP variability.

Chronic blockade of ACE with captopril did not change

variance or the spectral components of RR interval and SAP

in young rats. In addition, captopril did not affect the

reduced variability of SAP observed in aging rats. Although

the prolonged treatment with captopril did not affect the

reduced total variability of HR in aged rats, it did affect the

spectral components LF and HF, displacing the LF/HF ratio

toward predominance of HF. This finding indicates that the

sympatho/vagal balance was changed toward a predomi-

nance of vagal modulation of the heart due to chronic

blockage of ACE.

Overall, the data related to cardiovascular variability in

rats point to a disorder of the autonomic modulation of the

cardiovascular system associated with aging. Long-term

blockade of ACE with captopril seems to prevent some of

these alterations at the level of the heart.

Values obtained for reflex bradycardia in aged control

rats were smaller than those observed in young rats,

indicating that aging, up to 2 years, is accompanied by

depression of the vagal control of the heart, corroborating

previous observations from the literature (Bunag et al.,

1999; Irigoyen et al., 2000). Treatment with captopril during

2 months in young normotensive rats did not change the

baroreflex sensitivity as previously demonstrated in the

literature (Cheng et al., 1989), whereas a prolonged (20

months) treatment was able to prevent the depressed reflex

bradycardia, corroborating previous observations of Bunag

et al. (1999) with the ACE inhibitor lisinopril.

Evaluation of the baroreflex control of HR indicated that

the reflex tachycardia and bradycardia were significantly

depressed in aging untreated rats as compared to their young

counterparts. This reduction indicates an impairment of the

whole baroreflex arch. The methodological approach used

in the present study does not allow to determine what part of

the baroreflex arch is impaired, i.e. peripherally (afferents

and/or efferents) and/or centrally.

Chronic blockade of ACE with captopril did not prevent

in aged rats the attenuation of the reflex tachycardia, but it

V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–5554

did prevent the impairment of the reflex bradycardia. It is

well known that converting enzyme inhibitors improve the

depressed reflex bradycardia associated with diseases like

arterial hypertension and heart failure (Tomiyama et al.,

1998; Guasti et al., 2001; Binkley et al., 1993). This

favorable effect of captopril may be related to the blockade

of renin–angiotensin system within the central nervous

system (Montano et al., 1993; Rimoldi et al., 1994; Francis

et al., 2004), even though a peripheral effect on baror-

eceptors and/or autonomic nervous system cannot be ruled

out as well (Dias da Silva et al., 1994).

In conclusion, aging in rats is characterized by the

development of alterations of the sympathetic nervous

system that controls heart and vessels, characterized by a

reduced HR and AP variability, and attenuation of reflex

bradycardia and reflex tachycardia as well. These observa-

tions point out to a derangement of both segments of the

autonomic nervous system during aging, i.e. sympathetic

and parasympathetic arms of the reflex arch. Interestingly,

the new finding of the present study is that chronic treatment

with captopril decreased the LF/HF ratio leading to a shift of

the sympatho/vagal balance towards a predominance of

parasympathetic modulation associated with an increase of

baroreflex sensitivity, suggesting an improvement of cardiac

vagal function in aged rats treated with captopril. Therefore,

because it is well documented that reduced HR variability

and depressed baroreflex are associated with life threatening

cardiovascular risks, the findings obtained in the present

study suggest a benefic effect on long-term ACE inhibition

during aging.

Acknowledgements

Research supported by PRONEX I, CNPq, FAPESP and

FUNEPU. N.M. was supported by a COFIN 2003 Grant.

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